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Multi-Target Analysis and Design of Mitochondrial Metabolism.

Angione C, Costanza J, Carapezza G, Lió P, Nicosia G - PLoS ONE (2015)

Bottom Line: We find that the maximum ATP production is linked to a total consumption of NADH, and reaching the maximum amount of NADH leads to an increasing request of NADH from the external environment.Furthermore, the identifiability analysis characterizes the type and the stage of three monogenic diseases.Finally, we propose a new methodology to extend any constraint-based model using protein abundances.

View Article: PubMed Central - PubMed

Affiliation: Computer Laboratory-University of Cambridge, Cambridge, United Kingdom.

ABSTRACT
Analyzing and optimizing biological models is often identified as a research priority in biomedical engineering. An important feature of a model should be the ability to find the best condition in which an organism has to be grown in order to reach specific optimal output values chosen by the researcher. In this work, we take into account a mitochondrial model analyzed with flux-balance analysis. The optimal design and assessment of these models is achieved through single- and/or multi-objective optimization techniques driven by epsilon-dominance and identifiability analysis. Our optimization algorithm searches for the values of the flux rates that optimize multiple cellular functions simultaneously. The optimization of the fluxes of the metabolic network includes not only input fluxes, but also internal fluxes. A faster convergence process with robust candidate solutions is permitted by a relaxed Pareto dominance, regulating the granularity of the approximation of the desired Pareto front. We find that the maximum ATP production is linked to a total consumption of NADH, and reaching the maximum amount of NADH leads to an increasing request of NADH from the external environment. Furthermore, the identifiability analysis characterizes the type and the stage of three monogenic diseases. Finally, we propose a new methodology to extend any constraint-based model using protein abundances.

No MeSH data available.


Related in: MedlinePlus

Sensitivity analysis on the mitochondrial FBA model.The plot shows the mean and the standard deviation of the elementary effects computed through the Morris’ method applied on the upper bounds of the exchange reaction fluxes. The uptake rates are ranked according to their relative influence on the ATP production. The mitochondrial ATP production is highly sensitive to changes in the uptake rate of oxygen, HCO3, L-serine, and L-aspartate.
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pone.0133825.g008: Sensitivity analysis on the mitochondrial FBA model.The plot shows the mean and the standard deviation of the elementary effects computed through the Morris’ method applied on the upper bounds of the exchange reaction fluxes. The uptake rates are ranked according to their relative influence on the ATP production. The mitochondrial ATP production is highly sensitive to changes in the uptake rate of oxygen, HCO3, L-serine, and L-aspartate.

Mentions: In Fig 8, we show the result of the Morris method considering as input the uptake flux rates in the genome-scale metabolic network of the mitochondrion [17] discussed in Section 2. In the plot we report the mean and the standard deviation of the distribution of elementary effects for each input. The legend in the figure ranks the inputs from the most to the less important. These results were confirmed by the local robustness analysis [7], performed through perturbation of one input at a time. Finally, a pathway-oriented SA is reported in Fig S3 in S1 File for the model of Chlamydomonas reinhardtii [18] discussed in Section 1.


Multi-Target Analysis and Design of Mitochondrial Metabolism.

Angione C, Costanza J, Carapezza G, Lió P, Nicosia G - PLoS ONE (2015)

Sensitivity analysis on the mitochondrial FBA model.The plot shows the mean and the standard deviation of the elementary effects computed through the Morris’ method applied on the upper bounds of the exchange reaction fluxes. The uptake rates are ranked according to their relative influence on the ATP production. The mitochondrial ATP production is highly sensitive to changes in the uptake rate of oxygen, HCO3, L-serine, and L-aspartate.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4574446&req=5

pone.0133825.g008: Sensitivity analysis on the mitochondrial FBA model.The plot shows the mean and the standard deviation of the elementary effects computed through the Morris’ method applied on the upper bounds of the exchange reaction fluxes. The uptake rates are ranked according to their relative influence on the ATP production. The mitochondrial ATP production is highly sensitive to changes in the uptake rate of oxygen, HCO3, L-serine, and L-aspartate.
Mentions: In Fig 8, we show the result of the Morris method considering as input the uptake flux rates in the genome-scale metabolic network of the mitochondrion [17] discussed in Section 2. In the plot we report the mean and the standard deviation of the distribution of elementary effects for each input. The legend in the figure ranks the inputs from the most to the less important. These results were confirmed by the local robustness analysis [7], performed through perturbation of one input at a time. Finally, a pathway-oriented SA is reported in Fig S3 in S1 File for the model of Chlamydomonas reinhardtii [18] discussed in Section 1.

Bottom Line: We find that the maximum ATP production is linked to a total consumption of NADH, and reaching the maximum amount of NADH leads to an increasing request of NADH from the external environment.Furthermore, the identifiability analysis characterizes the type and the stage of three monogenic diseases.Finally, we propose a new methodology to extend any constraint-based model using protein abundances.

View Article: PubMed Central - PubMed

Affiliation: Computer Laboratory-University of Cambridge, Cambridge, United Kingdom.

ABSTRACT
Analyzing and optimizing biological models is often identified as a research priority in biomedical engineering. An important feature of a model should be the ability to find the best condition in which an organism has to be grown in order to reach specific optimal output values chosen by the researcher. In this work, we take into account a mitochondrial model analyzed with flux-balance analysis. The optimal design and assessment of these models is achieved through single- and/or multi-objective optimization techniques driven by epsilon-dominance and identifiability analysis. Our optimization algorithm searches for the values of the flux rates that optimize multiple cellular functions simultaneously. The optimization of the fluxes of the metabolic network includes not only input fluxes, but also internal fluxes. A faster convergence process with robust candidate solutions is permitted by a relaxed Pareto dominance, regulating the granularity of the approximation of the desired Pareto front. We find that the maximum ATP production is linked to a total consumption of NADH, and reaching the maximum amount of NADH leads to an increasing request of NADH from the external environment. Furthermore, the identifiability analysis characterizes the type and the stage of three monogenic diseases. Finally, we propose a new methodology to extend any constraint-based model using protein abundances.

No MeSH data available.


Related in: MedlinePlus